Anti-T-Cell Globulins Flop in Unrelated Stem Cell Transplants

GVHD reduced, but so was survival

Action Points

Anti-T-lymphocyte globulin (ATLG; Grafalon) was associated with worse progression-free and overall survival in patients who received hematopoietic stem cell transplants (HSCT) from matched, unrelated donors, according to a double-blind, randomized phase III study.

Note that the worsened survival with ATLG occurred despite reduction in incidence of graft-versus host disease (GVHD), which is a leading cause of morbidity in long-term survivors after HSCT.

Anti-T-lymphocyte globulin (ATLG; Grafalon) was associated with worse progression-free and overall survival in patients who received hematopoietic stem cell transplants from matched, unrelated donors, according to results of a double-blind, randomized phase III study.

This despite a reduction in incidence of graft-versus host disease (GVHD), reported Robert J. Soiffer, MD, of the Dana-Farber Cancer Institute in Boston, and colleagues in the Journal of Clinical Oncology.

Chronic GVHD is a leading cause of morbidity in long-term survivors after HCT. Previous studies suggested that ATLG improved chronic GVHD, but some trials reported increased relapse and infections.

For this manufacturer-sponsored study, the research team randomized 254 adult patients in North America and Australia to receive either ATLG (n=126) or placebo (n=128) before undergoing HLA-matched stem cell transplants. All patients had acute lymphoblastic leukemia, acute myeloid leukemia in complete morphologic remission, or myelodysplastic syndrome with <10% bone marrow blasts. Donors were unrelated and allele-level matched at HLA-A, -B, -C, and -DRB1.

Patients received one of three conditioning regimens selected by the treating physician:

All patients received tacrolimus (Prograf) and methotrexate as GVHD prophylaxis. If patients did not develop clinical GVHD, the researchers tapered tacrolimus on day 50 or later over a minimum of 26 weeks, then discontinued it.

On days -3, -2, and -1 before transplantation, patients received either ATLG at 20 mg/kg/day or saline. All patients received antihistamine and methylprednisolone 2 mg/kg on day -3 and 1 mg/kg on days -2 and -1.

The primary endpoint was moderate-to-severe chronic GVHD-free survival. There were no statistically significant differences between the groups, except the ATLG cohort had more females (52.4% versus 38.3%). Median follow-up was 24 months.

Incidences of both grade 2 to 4 acute GVHD and moderate-to-severe chronic GVHD were lower in patients who received ATLG over placebo (23% versus 40%, P=0.004, and 12% versus 33%, P<0.001, respectively).

The findings of poorer survival with ATLG appeared to contradict results of other published trials for reasons that were unclear. Some other studies included related donors, the authors noted. Some included cyclosporine; others used less ATLG, and some tested other anti-thymocyte globulin (ATG) products.

Another explanation may be related to the effect of the conditioning regimen on absolute lymphocyte counts, they added.

"We found a striking relationship between low absolute lymphocyte counts at the time of ATLG administration with inferior progression-free survival and overall survival," the authors wrote. Although they did not measure ATLG levels, low absolute lymphocyte counts before HCT might have resulted in less binding with subsequent delayed clearance and higher concentrations of ATLG after transplantation, they suggested. "Other investigators have correlated high ATG (thymoglobulin) levels after bone marrow transplantation with increased infectious complications," they added.

Results also may be different because the diseases included in the trials were different, noted Mohamad Mohty, MD, PhD, and Florent Malard, MD, PhD, of the Saint Antoine Hospital in Paris, in an accompanying editorial. In this study, only patients with acute leukemia or myelodysplastic syndrome were included; cohorts were more heterogeneous in the other studies. Other studies also had fewer patients with late-stage disease in the ATLG group, while the proportions of patients in each group with low-, intermediate-, and high-risk cytogenetics were similar in this study.

"It is reassuring to note that, despite some differences in HLA matching and GVHD prophylaxis in the report by Soiffer et al, the protective effect of the drug on chronic GVHD was conﬁrmed," Mohty and Malard wrote. "The effect of this agent on the quality of life of patients and decreased incidence of chronic GVHD-related long-term adverse effects are becoming progressively well established in routine clinical practice."

Further work into pre-transplant biomarkers like absolute lymphocyte counts are warranted to develop reliable dosing algorithms, they noted, adding that "the results of the study by Soiffer et al, combined with previous ﬁndings from different groups, are a step forward in the right direction."